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United States Patent PHARMACEUTICALS Dominic D. Micucci, Havertown, and Souren Avakian and Robert R. Brendel, Oreland, and Gustav J. Martin, Philadelphia, Pa., assignors to The National Drug Company, Philadelphia, Pa., a corporation of Delaware No Drawing. Application March 28, 1957 Serial No. 649,013

3 Claims. ('Cl. 260-558) QCHCHC ON wherein W is preferably hydrogen or halogen (e. g. chlorine, bromine, iodine and fluorine) but also may be lower alkyl (e. g. methyl ethyl, isopropyl, etc.) or lower alkoxy (e. g. methoxy, ethoxy, propoxy, etc.); R is hydrogen or lower alkyl (e. g. methyl, ethyl, isopropyl, etc); R is allyl; R is hydrogen, lower alkyl, lower alkenyl (preferably allylloraryl-lower alkyl; and R' is hydrogen, lower alkyl, lower alkenyl (preferably allyl), or aryllower alkyl. Preferred are those compounds containing at east one ethylenically unsaturated allyl group. Especially preferred are those compoundsin which R is hydrogen or methyl and R is allyl.

These compounds may be prepared by condensing the desired hydrocarbon halide (RX) with the desired dialkylmalonate (or an alkyl acetoacetate) in an anhydrous organic medium,,such as an alcohol (e. g. ethanol, isopropanol, etc.) or toluene, in the presence of equimolar amounts of an alkali metal, an alkali metal alkoxide, or an alkali metal hydride. The resulting product is then condensed with an alpha-phenylalkyl halide COOEt CH2 +RBr COOEt OOOEt CHR" 'JOOEt R l W 2,874,188 Patented Feb. 17, 1959 R COOEt W COOEt i hydrolysis R COOH W COOH l-decarbox.

R OOOH iHNR/IRIII R H R @ina-oos l w R! R!!! Where the R group in the alpha-phenylalkyl halide is other than hydrogen, the hydrocarbon halide (R'X) must be reacted with the dialkyl-malonate prior to the condensation with the alpha-phenylalkyl halide when the reaction is carried out in alcohol. In toluene, however, these alkylation steps may be carried out in either order.

This is possible because, in toluene, for instance, MeOH formed from the reaction of NaOMe and alpha-phenylalkylrnalonic ester is distilled out, hence, shifting the equilibrium:

i NaOMe+CHCH(COzEt)2 to the right eliminating the predominant RX-l-NaOMe reaction.

In the cases where the substituents in the molecule are such that the carbon atoms alpha and beta to the carboxarnide group are both asymmetric centers and diflen ent, then there exist two isomeric dl pairs which may be separated by fractional crystallization.

Although it is desirable to use stoichiometric quantities of the reactants in the condensation, considerable variation is possible in each step. Likewise, other reaction conditions such as temperature, pressure and the inert solvents'which are utilized, may be varied within wide limitations.

The compounds of the invention may be incorporated in the usual manner for ingestion, preferably by the oral route. Thus, the compounds may be tabletted or Cilcapsulated; and, if desired, they may be made into suspensions, elixirs or other such liquid form. The dosage which is utilized will vary with the particular patient being treated. The dosage unit forms may, therefore, be conveniently made up to contain about 50-200 mg. (prefer' ably about 50 mg.) per dosage unit of the active ingredient in lactose as the excipient or in 10% ethanol as the diluent, e. g. tablet, capsule. Tablets may, of course, be scored to provide for further fractional dosages.

Following are working examples presented as i1lustrative of the invention. However, these examples are not in any way limitative and canno restriction on the invention.

t be construed as any Example 1 A solution of 20.9 g. allylbenzylacetylchloride in 50 ml. anhydrous ethyl ether is added dropwise to a stirred solution of 16 g. diethylamine in 200 ml. anhydrous ethyl ether. The reaction mixture is stirred for 2 hours, allowed to stand over night and then filtered. The filtrate is washed several times with water, dried over anhydrous Na SO and distilled. The N,N-diethylallylbenzylacetamide, B. P. 115-117 amounted to about 18 g.

Examples 2-11 Following the procedures of Example 1 and substituting the equivalent reactants for those used in the reference example, the following compounds are prepared. The acetyl halide reactant used is preferably acetylchloride; however, any other acetyl halide, in equivalent stoichiometric amounts, may be substituted, particularly the acetylbromide. Thus, for example, allylbenzylacetylbromide may be substituted for the corresponding chloride.

This invention may be variously otherwise embodied within the scope of the appended claims.

We claim:

1. Compounds of the group consisting of those having wherein W is a member of the group consisting of hydrogen, halogen, methyl and methoxy; R is a member of the group consisting of hydrogen, lower alkyl; and R" and R' are members of the group consisting of hydrogen, 20 lower alkyl, lower alkenyl and aryl-lower alkyl radicals.

2. Alpha-allyl-alpha-benzylacetamide. 3. Alpha-allyl-alpha-(alpha-phenylethy)-acetamide.

R R R R'" B. PJmm. M. P., degrees 2 H CH:=CHCH: CHg=CHCHg- GH,=cHcH, 125-7/0.5 3 H CHr-"GHCHP CHsCHz- (CHaCHg)N(J=O 118192/0.5

r H, oHFGHoHromcH,- 169-173/0. 7 CHr-"CHCH H qSCHr 71-72 CH2: CHzqbCHz- CH:- 76-77 CH;=CHCH, omen,- 0 =OH= 122124/0.8 OH=OHCH; OH3OH2- GHHGHP I 125-127/0.s 0H,=GHOH,- CHz=CHCHg OHQ=CHGH: 134136/0.5 0H,=oHoH,- H Hz- 129-1a0/0. CH=CHCH- OH3- CHre-107 0. 5

Examples 12-20 References Cited in the file of this patent Following the procedures of Example 2, the following UNITED STATES PATENTS compounds are prepared, covered by the structural fO 2 413 493 Flisik et 1 31, 1946 mula: 2,459,706 King Jan. 18, 1949 R1 /R2 Qimonoor FOREIGN PATENTS X ('11:, r: 256,756 Germany Feb. 20, 1913 5, 7,591 Great Britain Nov. 16, 1911 lg 368,590 Great Britain Mar. 10, 1932 B OTHER REFERENCES X Hm I. A. c. s., V01. 60, pp. 465-467 1938).

J. A. C. 8., vol. 72, pp. 1488-1489 (1950). H H Jour. Chem. Soc. (London), pp. 2750-2758 (1926). g g I. Prak. Chem., vol. 71, pp. 311 and 316 (1905). H H Ramart: Annales des Chemie, vol. 8, series 10 3g; 5 1927 pp. 268 and 272. CH3 H Beilsteins Handbook Org. Chem., 4th ed., vol. 9, 2nd (8%??5- E suppL, page 421 1949 Y 

1. COMPOUNDS OF THE GROUP CONSISTING OF THOSE HAVING THE GENERAL FORMULA: 